DESCRIPTION :(Adapted from Applicant's Abstract) Aberrant expression of inflammatory cytokines during the HIV-1 infection has been implicated in the pathogenesis of AIDS. However, the molecular mechanism by which HIV-1 modulates the expression of cytokine genes has not completely been clarified. They have recently shown (Popik & Pitha, 1996) that binding of HIV-1 virions or gp 120 to the CD4 receptors on T-cells results in the association of Lck (which is associated with CD4 receptor) with Raf-1 kinase which leads to Raf-1 activation. The activation depends on the presence of functioning CD4 receptors and is not Ras-mediated. They have further demonstrated (see preliminary results) that this novel signaling pathway is functional and results in the activation of several nuclear transcription factors (AP-1, NF-kB, C/EBP) with the consequent activation of transcription of several cytokine and chemokine genes as well as Fas ligand. Although we have unambiguously demonstrated that this pathway is mediated by the CD4 receptors, the question arises whether the binding of HIV-1 virions to the newly described HIV-1 coreceptor, CXCR4 participates or contributes to this signaling. Since the syncytium-inducing viruses that emerge in the later stages of HIV-1 infection use CXCR4 as coreceptor, it is likely that binding of these viruses to this coreceptor induces intracellular signaling, contributing to the activation of inflammatory genes and to the rapid decline of CD4+ T-cells. The studies proposed are designed to characterize and analyze the unique signaling pathway activated by HIV-1 binding to the CXCR4 receptor. In Aim #1, they will analyze the CXCR4-mediated expression of inflammatory genes and induction of nuclear transcription of nuclear transcription factors after binding of HIV-1. In Aim #2, they will investigate the role of CXCR4 signaling in the infection of peripheral blood CD4+ naive and memory T lymphocytes. In Aim #3, they plan to identify CXCR4 sequences involved in HIV-1 mediated signaling. Finally, in Aim #4, they will investigate the molecular mechanism of SDF-1 inhibition of HIV-1 induced signaling. They believe that this study will contribute to our better understanding of HIV-1-induced pathogenicity and will provide a rational basis for new approaches to inhibit HIV replication.